Quantitative Structure-Permeation Relationships (QSPeRs) to Predict Skin Permeation: A Critical Evaluation

Purpose. Development of reliable mathematical models to predict skin permeability remains a challenging objective. This article examines some of the existing algorithms and critically evaluates their statistical relevance. Methods. Complete statistics were recalculated for a number of published models using a stepwise multiple regression procedure. The predictivity of the models was obtained by cross-validation using a "leave-one-out” deletion pattern. The relative contribution of each independent variable to the models was calculated by a standardization procedure. Results. The heterogeneity of the data in terms of skin origin and experimental conditions has been shown to contribute to the residual variance in existing models. Furthermore, rigorous statistics demonstrate that some published models are based on nonsignificant parameters. As such, they afford misleading mechanistic insight and will lead to over-interpretation of the data. Conclusions. The large number of published models reflects the need for predictive tools in cutaneous drug delivery and toxicology. However, such models are more reliable when confined within well-defined chemical classes, and their applicability is often limited by the narrow property space of the set of permeants under stud

Quantitative Structure-Permeation Relationships for Solute Transport Across Silicone Membranes

Purpose. The purpose of this work was to assess the molecular properties that influence solute permeation across silicone membranes and to compare the results with transport across human skin. Methods. The permeability coefficients (log K p) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure-permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2-dichloroethane/water partition coefficients (Δlog P oct-dce), which reported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential. Results. The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across silicone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis. Conclusion. The key molecular properties that control solute permeation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here, a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barrier

Neoadjuvant Chemoradiotherapy versus Chemotherapy for Gastroesophageal Junction Adenocarcinoma; Which Is the Optimal Treatment Option?

Background: Locally advanced gastroesophageal junction adenocarcinoma (GEJ) is treated with either perioperative chemotherapy (CT) or preoperative radiochemotherapy (RCT) followed by surgery. The aim of this study was to compare pathologic response and long-term outcomes in junction adenocarcinoma treated with neoadjuvant RCT versus CT. Methods: All patients with locally advanced GEJ adenocarcinoma treated with neoadjuvant treatment (NAT) followed by surgery between 2009 and 2018 were retrospectively analyzed. Results: A total of 94 patients were included, 67 (71.2%) RCT and 27 (28.8%) CT. Complete pathologic response was more frequent in RCT patients (13.4% vs. 7.4%, p = 0.009) with a trend to better lymph node control (ypN0) (55.2% vs. 33.3%; p = 0.057). RCT offered no benefit in R0 resection (66.7% vs. 72.1% CT, p = 0.628) and was related to higher postoperative cardiovascular complications (35.8% vs. 11.1%; p = 0.017). Long-term overall and disease-free survival were similar (5-year OS 61.1% RCT vs. 75.7% CT, p = 0.259; 5-year DFS 33.5% RCT vs. 22.8% CT; p = 0.763). NAT type was neither independently associated with pathologic response nor long-term survival. Discussion: Patients with locally advanced GEJ adenocarcinoma treated with RCT had more postoperative cardiovascular complications but higher rates of complete pathologic response and a trend to superior locoregional lymph node control. This did not translate in a survival or recurrence benefit